Laparoscopic liver resection for hepatocellular carcinoma in cirrhotic patients: single center experience of 90 cases

Background

Hepatocellular carcinoma (HCC) with or without underlying liver disease can be treated by surgical resection. The aim of this study was to evaluate the feasibility, morbidity and mortality of a laparoscopic approach in cirrhotic patients with HCC.

Methods

From 2004 to September 2014, 90 patients underwent a laparoscopic liver resection (LLR) for HCC. Data were collected in a prospectively maintained database since 2001. Preoperative patient evaluation was based on a multidisciplinary team meeting assessment.

Results

Median age was 63 years; 67 (74.4%) patients were male. Median body mass index (BMI) was 26.7. Underlying liver disease was known in 68 patients: in 46 patients’ hepatitis C virus (HCV)-related, in 15 patients to hepatitis B virus (HBV)-related, in 5 patients alcohol-related. Child-Pugh Score was of grade A in 85 patients and of grade B in 5 patients; 63 patients had a Model for End-stage Liver Disease (MELD) <10 and 27 patients MELD >10. A total of 18 left lateral sectionectomies, 1 left hepatectomy and 71 wedge resections or segmentectomies were performed. Conversion to laparotomy was necessary in 7 (7.7%) patients (five cases for bleeding and two cases for oncological reasons). In 90 patients, 98 HCC nodules were resected: 79 patients had one nodule, 8 patients had two nodules and 1 patient had three nodules. HCC nodules medium diameter was 29 mm (range, 4-100 mm) with median value of 25 mm. Tumor margins distance was 16 mm (range, 0-35 mm) with a median of 5 mm. Seventy nodules were located within the anterior sectors and 28 nodules within the posterior sectors.

Conclusions

LLR for HCC can be performed with acceptable morbidity in patients with underlying liver disease. The use of laparoscopic surgery in cirrhotic patients may be proposed as the first-line treatment for HCC or as bridge treatment before liver transplantation.     

A simple, noninvasively determined index predicting hepatic failure following liver resection for hepatocellular carcinoma

Background  A novel index, the serum aspartate aminotransferase activity/platelet count ratio index (APRI), has been identified as a biochemical surrogate for histological fibrogenesis and fibrosis in cirrhosis. We evaluated the ability of preoperative APRI to predict hepatic failure following liver resection for hepatocellular carcinoma. Methods  Potential preoperative risk factors for postoperative hepatic failure (hepatic coma with hyperbilirubinemia, four patients; intractable pleural effusion or ascites, 30 patients; and variceal bleeding, one patient) as well as APRI were evaluated in 366 patients undergoing liver resection for hepatocellular carcinoma. Prognostic significance was determined by univariate and multivariate analyses. Results  Hepatic failure developed postoperatively in 30 patients, causing death in four. APRI correlated with histological intensity of hepatitis activity and degree of hepatic fibrosis, and was significantly higher in patients who developed postoperative hepatic failure than in others without failure. Risk of postoperative hepatic failure increased as the serum albumin concentration and platelet count decreased and as indocyanine green retention rate at 15 min, aspartate and alanine aminotransferase activities, and APRI increased. Only APRI was an independent preoperative factor on multivariate analysis. Of the four patients who died of postoperative hepatic failure, three had an APRI of at least 10. Conclusions  Preoperative APRI independently predicted hepatic failure following liver resection for hepatocellular carcinoma. Patients with an APRI of 10 or more have a high risk of postoperative hepatic failure.     

Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria: a meta-analysis of 18,421 patients

BackgroundOutcomes after liver resection (LR) and liver transplantation (LT) for hepatocellular carcinoma (HCC) are heterogenous and may vary by region, over time periods and disease burden. We aimed to compare overall survival (OS) and disease-free survival (DFS) between LT versus LR for HCC within the Milan criteria.MethodsTwo authors independently searched Medline and Embase databases for studies comparing survival after LT and LR for patients with HCC meeting the Milan criteria. Meta-analyses and metaregression were conducted using random-effects models.ResultsWe screened 2,278 studies and included 35 studies with 18,421 patients. LR was associated with poorer OS [hazard ratio (HR) =1.44; 95% confidence interval (CI): 1.14–1.81; P<0.01] and DFS (HR =2.71; 95% CI: 2.23–3.28; P<0.01) compared to LT, with similar findings among intention-to-treat (ITT) studies. In uninodular disease, OS in LR was comparable to LT (P=0.13) but DFS remained poorer (HR =2.95; 95% CI: 2.30–3.79; P<0.01). By region, LR had poorer OS versus LT in North America and Europe (P≤0.01), but not Asia (P=0.25). LR had inferior survival versus LT in studies completed before 2010 (P=0.01), but not after 2010 (P=0.12). Cohorts that underwent enhanced surveillance had comparable OS after LT and LR (P=0.33), but cohorts undergoing usual surveillance had worse OS after LR (HR =1.95; 95% CI: 1.24–3.07; P<0.01).ConclusionsMortality after LR for HCC is nearly 50% higher compared to LT. Survival between LR and LT were similar in uninodular disease. The risk of recurrence after LR is threefold that of LT.     

Small for size liver remnant following resection: prevention and management

In the latest decades an important change was registered in liver surgery, however the management of liver cirrhosis or small size hepatic remnant still remains a challenge. Currently post-hepatectomy liver failure (PLF) is the major cause of death after liver resection often associated with sepsis and ischemia-reperfusion injury (IRI). ‘‘Small-for-size’’ syndrome (SFSS) and PFL have similar mechanism presenting reduction of liver mass and portal hyper flow beyond a certain threshold. Few methods are described to prevent both syndromes, in the preoperative, perioperative and postoperative stages. Additionally to portal vein embolization (PVE), radiological examinations (mainly CT and/or MRI), and more recently 3D computed tomography are fundamental to quantify the liver volume (LV) at a preoperative stage. During surgery, in order to limit parenchymal damage and optimize regenerative capacity, some hepatoprotective measures may be employed, among them: intermittent portal clamping and hypothermic liver preservation. Regarding the treatment, since PLF is a quite complex disease, it is required a multi-disciplinary approach, where it management must be undertaken in conjunction with critical care, hepatology, microbiology and radiology services. The size of the liver cannot be considered the main variable in the development of liver dysfunction after extended hepatectomies. Additional characteristics should be taken into account, such as: the future liver remnant; the portal blood flow and pressure and the exploration of the potential effects of regeneration preconditioning are all promising strategies that could help to expand the indications and increase the safety of liver surgery.     

A scoring system for the assessment of the risk of mortality after partial hepatectomy in patients with chronic liver dysfunction

Background/purpose The aim of this study is to evaluate a new scoring system, called the chronic liver dysfunction (CLD) score, for prediction of the surgical risk of partial hepatectomy in patients with chronic liver damage. Morbidity and mortality rates after gastroenterological surgery are high in patients with hepatic cirrhosis. Accordingly, it is very important to assess the surgical risk in such patients before surgery. Although the Child classification (or Child–Pugh score) has been a standard system, it did not always accurately predict patients at the risk of mortality after gastroenterological surgery, especially partial hepatectomy.Methods In 1985, we established a new system called the CLD score, reviewing the patients undergoing gastroenterological operations at one hospital. In the present study, we prospectively used the CLD score in 256 consecutive patients with chronic liver dysfunction who were treated surgically by partial hepatectomy, and investigated the usefulness of the CLD score concerning mortality. The results were compared with those of the Child–Pugh score (C-P score).Results After major hepatectomy, all the patients with CLD score exceeding 1.5 died of hepatic failure. After minor hepatectomy, all the patients with CLD score exceeding 2.5 died of hepatic failure. On the other hand, C-P score did not predict the outcome in these patients.Conclusions Compared with the C-P score, which was considered the gold standard scoring system for assessing surgical risk for patients with chronic liver dysfunction, our CLD score provides a more reliable assessment of the risk of partial hepatectomy.     

Development of a machine learning model to predict early recurrence for hepatocellular carcinoma after curative resection

BackgroundEarly recurrence is common for hepatocellular carcinoma (HCC) after surgical resection, being the leading cause of death. Traditionally, the COX proportional hazard (CPH) models based on linearity assumption have been used to predict early recurrence, but predictive performance is limited. Machine learning models offer a novel methodology and have several advantages over CPH models. Hence, the purpose of this study was to compare random survival forests (RSF) model with CPH models in prediction of early recurrence for HCC patients after curative resection.MethodsA total of 4,758 patients undergoing curative resection from two medical centers were included. Fifteen features including age, gender, etiology, platelet count, albumin, total bilirubin, AFP, tumor size, tumor number, microvascular invasion, macrovascular invasion, Edmondson-Steiner grade, tumor capsular, satellite nodules and liver cirrhosis were used to construct the RSF model in training cohort. Discrimination, calibration, clinical usefulness and overall performance were assessed and compared with other models.ResultsFive hundred survival trees were used to generate the RFS model. The five highest Variable Importance (VIMP) were tumor size, macrovascular invasion, microvascular invasion, tumor number and AFP. In training, internal and external validation cohort, the C-index of RSF model were 0.725 [standard errors (SE) =0.005], 0.762 (SE =0.011) and 0.747 (SE =0.016), respectively; the Gönen & Heller’s K of RSF model were 0.684 (SE =0.005), 0.711 (SE =0.008) and 0.697 (SE =0.014), respectively; the time-dependent AUC (2 years) of RSF model were 0.818 (SE =0.008), 0.823 (SE =0.014) and 0.785 (SE =0.025), respectively. The RSF model outperformed early recurrence after surgery for liver tumor (ERASL) model, Korean model, American Joint Committee on Cancer tumor-node-metastasis (AJCC TNM) stage, Barcelona Clinic Liver Cancer (BCLC) stage and Chinese stage. The RSF model is capable of stratifying patients into three different risk groups (low-risk, intermediate-risk, high-risk groups) in the training and two validation cohorts (all P<0.0001). A web-based prediction tool was built to facilitate clinical application (https://recurrenceprediction.shinyapps.io/surgery_predict/).ConclusionsThe RSF model is a reliable tool to predict early recurrence for patients with HCC after curative resection because it exhibited superior performance compared with other models. This novel model will be helpful to guide postoperative follow-up and adjuvant therapy.     

Mortality Risk Factors Among Patients With Cirrhosis and a Low Model for End‐Stage Liver Disease Sodium Score (≤15): An Analysis of Liver Transplant Allocation Policy Using Aggregated Electronic Health Record Data

Although the Model for End‐Stage Liver Disease sodium (MELD Na) score is now used for liver transplant allocation in the United States, mortality prediction may be underestimated by the score. Using aggregated electronic health record data from 7834 adult patients with cirrhosis, we determined whether the cause of cirrhosis or cirrhosis complications was associated with an increased risk of death among patients with a MELD Na score ≤15 and whether patients with the greatest risk of death could benefit from liver transplantation (LT). Over median follow‐up of 2.3 years, 3715 patients had a maximum MELD Na score ≤15. Overall, 3.4% were waitlisted for LT. Severe hypoalbuminemia, hepatorenal syndrome, and hepatic hydrothorax conferred the greatest risk of death independent of MELD Na score with 1‐year predicted mortality >14%. Approximately 10% possessed these risk factors. Of these high‐risk patients, only 4% were waitlisted for LT, despite no difference in nonliver comorbidities between waitlisted patients and those not listed. In addition, risk factors for death among waitlisted patients were the same as those for patients not waitlisted, although the effect of malnutrition was significantly greater for waitlisted patients (hazard ratio 8.65 [95% CI 2.57–29.11] vs. 1.47 [95% CI 1.08–1.98]). Using the MELD Na score for allocation may continue to limit access to LT.     

Minimally invasive liver resection for huge (≥10 cm) tumors: an international multicenter matched cohort study with regression discontinuity analyses

BackgroundThe application and feasibility of minimally invasive liver resection (MILR) for huge liver tumours (≥10 cm) has not been well documented.MethodsRetrospective analysis of data on 6,617 patients who had MILR for liver tumours were gathered from 21 international centers between 2009–2019. Huge tumors and large tumors were defined as tumors with a size ≥10.0 cm and 3.0–9.9 cm based on histology, respectively. 1:1 coarsened exact-matching (CEM) and 1:2 Mahalanobis distance-matching (MDM) was performed according to clinically-selected variables. Regression discontinuity analyses were performed as an additional line of sensitivity analysis to estimate local treatment effects at the 10-cm tumor size cutoff.ResultsOf 2,890 patients with tumours ≥3 cm, there were 205 huge tumors. After 1:1 CEM, 174 huge tumors were matched to 174 large tumors; and after 1:2 MDM, 190 huge tumours were matched to 380 large tumours. There was significantly and consistently increased intraoperative blood loss, frequency in the application of Pringle maneuver, major morbidity and postoperative stay in the huge tumour group compared to the large tumour group after both 1:1 CEM and 1:2 MDM. These findings were reinforced in RD analyses. Intraoperative blood transfusion rate and open conversion rate were significantly higher in the huge tumor group after only 1:2 MDM but not 1:1 CEM.ConclusionsMILR for huge tumours can be safely performed in expert centers It is an operation with substantial complexity and high technical requirement, with worse perioperative outcomes compared to MILR for large tumors, therefore judicious patient selection is pivotal.     

Hepatocellular carcinoma in Child's A cirrhosis: a retrospective analysis of matched pairs following liver transplantation vs. liver resection according to the intention‐to‐treat principle

This is the first matched pair analysis on the puzzling clinical problem of whether to perform liver transplantation (LT) or liver resection (LR) for Child's A hepatocellular carcinoma (HCC) patients. A total of 201 patients diagnosed with HCC and Child's A liver cirrhosis were treated with LT transarterial chemoembolization (TACE) or LR between 1998 and 2012. To achieve the most accurate study design, two groups of 57 patients were matched retrospectively according to their tumor characteristics detected by the initial computerized tomography (CT) scan. Sixteen of 57 LT candidates were not transplanted due to tumor progress during pre‐treatment (TACE). Nevertheless, the retrospective analysis of the matched pairs according to the intention‐to‐treat principle resulted in a better five‐yr overall survival (OS) rate of 54.3% for the group of LT candidates compared with 35.7% for those receiving LR (p = 0.19). In patients meeting the University of California, San Francisco (UCSF) criteria, five‐yr OS reached 58.4% after LT and 45.1% after LR (p = 0.56). For Milan criteria (MC) patients, LT resulted in 57.9% and LR in 42% five‐yr OS rate (p = 0.29). In conclusion, the finding of a better OS rate in LT was not statistically significant. There was also a selection bias in favor of LT, which may have influenced the OS. Therefore, particularly in regard to organ scarcity, LR remains a viable treatment option for respectable HCC in Child's A cirrhosis.     

Albumin-bilirubin grade predicts the outcomes of liver resection versus radiofrequency ablation for very early/early stage of hepatocellular carcinoma

Background and purpose

Whether liver resection or ablation should be the first-line treatment for very early/early hepatocellular carcinoma (HCC) in patients who are candidates for both remains controversial. The aim of this study was to determine if the newly-developed Albumin-Bilirubin (ALBI) grade might help in treatment selections and to evaluate the survival of patients treated with liver resection and radiofrequency ablation (RFA).

National Outcomes of Liver Transplantation for Model for End‐Stage Liver Disease Score ≥40: The Impact of Share 35

In certain regions of the United States in which organ donor shortages are persistent and competition is high, recipients wait longer and are critically ill with Model for End‐Stage Liver Disease (MELD) scores ≥40 when they undergo liver transplantation. Recent implementation of Share 35 has increased the percentage of recipients transplanted at these higher MELD scores. The purpose of our study was to examine national data of liver transplant recipients with MELD scores ≥40 and to identify risk factors that affect graft and recipient survival. During the 12‐year study period, 5002 adult recipients underwent deceased donor whole‐liver transplantation. The 1‐, 3‐, 5‐ and 10‐year graft survival rates were 77%, 69%, 64% and 50%, respectively. The 1‐, 3‐, 5‐ and 10‐year patient survival rates were 80%, 72%, 67% and 53%, respectively. Multivariable analysis identified previous transplant, ventilator dependence, diabetes, hepatitis C virus, age >60 years and prolonged hospitalization prior to transplant as recipient factors increasing the risk of graft failure and death. Donor age >30 years was associated with an incrementally increased risk of graft failure and death. Recipients after implementation of Share 35 had shorter waiting times and higher graft and patient survival compared with pre–Share 35 recipients, demonstrating that some risk factors can be mitigated by policy changes that increase organ accessibility.     

Functional status,healthcare utilization,and the costs of liver transplantation

The Model for End‐Stage Liver Disease (MELD) score predicts higher transplant healthcare utilization and costs; however, the independent contribution of functional status towards costs is understudied. The study objective was to evaluate the association between functional status, as measured by Karnofsky Performance Status (KPS), and liver transplant (LT) costs in the first posttransplant year. In a cohort of 598 LT recipients from July 1, 2009 to November 30, 2014, multivariable models assessed associations between KPS and outcomes. LT recipients needing full assistance (KPS 10%‐40%) vs being independent (KPS 80%‐100%) were more likely to be discharged to a rehabilitation facility after LT (22% vs 3%) and be rehospitalized within the first posttransplant year (78% vs 57%), all P < .001. In adjusted generalized linear models, in addition to MELD (P < .001), factors independently associated with higher 1‐year post‐LT transplant costs were older age, poor functional status (KPS 10%‐40%), living donor LT, pre‐LT hemodialysis, and the donor risk index (all P < .001). One‐year survival for patients in the top cost decile was 83% vs 93% for the rest of the cohort (log rank P < .001). Functional status is an important determinant of posttransplant resource utilization; therefore, standardized measurements of functional status should be considered to optimize candidate selection and outcomes.     

MELD as a metric for survival benefit of liver transplantation

Currently, there is debate among the liver transplant community regarding the most appropriate mechanism for organ allocation: urgency‐based (MELD) versus utility‐based (survival benefit). We hypothesize that MELD and survival benefit are closely associated, and therefore, our current MELD‐based allocation already reflects utility‐based allocation. We used generalized gamma parametric models to quantify survival benefit of LT across MELD categories among 74 196 adult liver‐only active candidates between 2006 and 2016 in the United States. We calculated time ratios (TR) of relative life expectancy with transplantation versus without and calculated expected life years gained after LT. LT extended life expectancy (TR > 1) for patients with MELD > 10. The highest MELD was associated with the longest relative life expectancy (TR = _1.051.20_1.37 for MELD 11‐15, _2.292.49_2.70 for MELD 16‐20, _5.305.72_6.16 for MELD 21‐25, _15.1216.35_17.67 for MELD 26‐30; _39.2643.21_47.55 for MELD 31‐34; _120.04128.25_137.02 for MELD 35‐40). As a result, candidates with the highest MELD gained the most life years after LT: 0.2, 1.5, 3.5, 5.8, 6.9, 7.2 years for MELD 11‐15, 16‐20, 21‐25, 26‐30, 31‐34, 35‐40, respectively. Therefore, prioritizing candidates by MELD remains a simple, effective strategy for prioritizing candidates with a higher transplant survival benefit over those with lower survival benefit.     

Impact of the Pediatric End‐Stage Liver Disease (PELD) growth failure thresholds on mortality among pediatric liver transplant candidates

The Pediatric End‐Stage Liver Disease (PELD) score is intended to determine priority for children awaiting liver transplantation. This study examines the impact of PELD's incorporation of “growth failure” as a threshold variable, defined as having weight or height <2 standard deviations below the age and gender norm (z‐score <2). First, we demonstrate the “growth failure gap” created by PELD's current calculation methods, in which children have z‐scores <2 but do not meet PELD's growth failure criteria and thus lose 6‐7 PELD points. Second, we utilized United Network for Organ Sharing (UNOS) data to investigate the impact of this “growth failure gap.” Among 3291 pediatric liver transplant candidates, 26% met PELD‐defined growth failure, and 17% fell in the growth failure gap. Children in the growth failure gap had a higher risk of waitlist mortality than those without growth failure (adjusted subhazard ratio [SHR] 1.78, 95% confidence interval [95% CI] 1.05‐3.02, P = .03). They also had a higher risk of posttransplant mortality (adjusted HR 1.55, 95% CI 1.03‐2.32, P = .03). For children without PELD exception points (n = 1291), waitlist mortality risk nearly tripled for those in the gap (SHR 2.89, 95% CI 1.39‐6.01, P = .005). Current methods for determining growth failure in PELD disadvantage candidates arbitrarily and increase their waitlist mortality risk. PELD should be revised to correct this disparity.     

MELD-Na评分对逆行灌注法原位肝移植术后早期急性肾损伤发生的预测作用

目的  探讨术前终末期肝病模型联合血清钠（MELD-Na）评分对肝移植术后早期急性肾损伤（AKI）发生率的预测效果。方法  回顾性分析315例行经下腔静脉逆行灌注法原位肝移植受者的临床资料。根据术前MELD-Na评分,将患者分为3组：A组为MELD-Na评分≤ 10分（115例）;B组为10分20分（82例）。比较3组受者术前、术中各项指标。术前指标包括血清肌酐（Scr）、血尿素氮（BUN）、白蛋白（Alb）、总胆红素（TB）、凝血酶原时间国际标准化比值（PT-INR）、平均动脉压（MAP）、血清Na⁺等;术中指标包括手术时间、腔静脉阻断时间、出血量、输红细胞量、输血浆量、总补液量等。统计3组受者肝移植术后早期AKI的发生率及分期情况,并采用Spearman等级相关分析术前MELD-Na评分与AKI分期之间的关系。结果  3组受者术前BUN、Alb、TB、PT-INR、MAP、Na⁺比较,差异均有统计学意义（均为P < 0.05）,术中的腔静脉阻断时间、出血量、输红细胞量、输血浆量比较,差异亦均有统计学意义（均为P < 0.05）。315例肝移植受者,术后早期1周内AKI发生率64.8%（204/315）,其中A、B、C组术后AKI发生率分别为43%（49/115）、71%（84/118）、87%（71/82）,3组间比较差异有统计学意义（P < 0.05）。经Spearman等级相关分析,术前MELD-Na评分与AKI分期存在正相关（r=0.442,P=0.000）。结论  MELD-Na评分不仅可以作为术前病情评估指标,也是术后发生AKI的重要预测指标。